ABSTRACT The long-range goal of this grant is to determine the cellular and molecular events that lead to the generation of specific cell types in the vertebrate retina. In this renewal we focus upon plasticity and commitment of photoreceptor progenitors and precursors, with an emphasis on retinoid signaling as a mechanism for controlling photoreceptor fate. During the current funding period we demonstrated that retinoid treatment causes ?dedicated cone progenitors? to generate rods, and that the tandemly duplicated zebrafish long wavelength-sensitive (?red? or L) opsin genes, LWS1 and LWS2 (orthologous to the human L/M cone opsin array) can be regulated by retinoids. These findings offer opportunities to probe the plasticity of photoreceptor progenitors, determine mechanisms through which differential expression of tandemly duplicated opsin genes is achieved, and suggest the enticing prospect of targeted pharmacological manipulation of photoreceptor phenotypes and ratios of these phenotypes in the treatment of retinal degenerative diseases. Retinoid receptors are highly conserved among vertebrates. The zebrafish is exceptional for studies involving small molecules such as retinoids, and offers genetic resources for manipulation and measurement of retinoid signaling, and for identification of cone progenitors and specific photoreceptor types. Naturally occurring and synthetic retinoids already see use in the clinic and in photoreceptor differentiation protocols from human ES and iPS cells, making translational applications of our findings not only likely, but rapid. Our proposed studies will test the central hypothesis that retinoid signaling via specific receptors is an endogenous regulatory mechanism underlying photoreceptor progenitor plasticity, and apply this information in the contexts of regenerative and stem cell approaches for photoreceptor replacement, with the following Specific Aims: 1. Identify and analyze retinoid signaling-dependent plastic states in cone progenitors. 2. Determine the mechanisms through which retinoid signaling regulates cone progenitor plasticity. 3. Determine the fates and plasticity of cone progenitors during retinal regeneration. These studies will reveal cellular and molecular mechanisms underlying plasticity of photoreceptor progenitors, generating information necessary to manipulate photoreceptor phenotypic fates in concert with the application of cell replacement therapies for human retinal degenerations.